RMC-4550 / Revolution Medicines - LARVOL DELTA

The efficacy of NST-628, a non-degrading pan-RAF/MEK molecular glue, and MEK inhibitors for overcoming acquired osimertinib resistance mediated by TRIM24-BRAF fusions in EGFR mutant NSCLC (AACR 2025) - "Next, we utilized a panel of compounds targeting the RAS/RAF/MAPK pathway including agents targeting pan-RAS (RMC-6236 and RMC-7977), SHP2 (RMC-4550), BRAF (dabrafenib, encorafenib, tovorafenib and vemurafenib), pan-RAF (TAK-632), MEK (binimetinib, cobimetinib, selumetinib and trametinib), pan-RAF/MEK (NST-628) and assessed whether targeting signal transduction molecule downstream of EGFR could overcome this adaptative resistance mechanism. TRIM24-BRAF expressing cells showed minimal sensitivity to BRAF, SHP2 or RAS targeting single agents. Taken together, our findings indicate that expression of TRIM24-BRAF fusion induce osimertinib resistance in EGFR mutant NSCLC and targeting the MEK pathway using trametinib or NST-628 can overcome osimertinib resistance in this setting."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • EGFR • TRIM24

Combining RAS(ON) G12C-selective and RAS(ON) multi-selective inhibitors overcomes sotorasib resistance driven byKRASG12C amplification or NRASG13R mutation (AACR 2025) - "Amplification of the KRASG12C mutant allele and acquisition of NRAS mutations have been reported as resistance mechanisms in tumors progressing on sotorasib and adagrasib...We generated five sotorasib-resistant cell lines from relapsed tumors of sotorasib-treated H358 xenografts (MR1-MR5) and two vehicle-treated tumors (MV1 and MV2). We created an additional isogenic cell line model, H358-MX1, by treating H358 cells with sotorasib and a SHP2 inhibitor, RMC-4550...In H358-MX1 mouse xenografts, RMC-7977 + RMC-4998 significantly inhibited tumor growth compared to single-agent treatments or other combination regimens. These preclinical data suggest that combination of RAS(ON) mutant-selective and RAS(ON) multi-selective inhibitors overcome resistance to KRASG12C (OFF) inhibitors driven by KRASG12C amplification and secondary NRASG13R mutation in KRASG12C mutated lung cancer models."

Lung Cancer • Oncology • Solid Tumor • KRAS • MX1 • NRAS

Preclinical evaluation of RAS pathway inhibitors in gastroesophageal adenocarcinoma (AACR 2025) - "The allosteric SHP2 inhibitor RMC-4550 demonstrated an IC50 of 0.08-6.67 μM in KRASAMP and KRASG12D lines...There was no adaptive signaling through PI3K pathways based on suppressed p-AKT levels, in comparison to trametinib which resulted in increases in pAKT. The RAF/MEK clamp VS-6766 also inhibits signaling through MAPK as evidenced by decreased p-AKT, and an EC50 for p-ERK of 131.83 nM (KRASAMP) and 10.4725 nM (KRASMUT) GEA cells...Our results suggest that combination strategies will be essential to overcome adaptive resistance and maximize therapeutic benefit in KRASAMP cells. Future in vivo studies will validate the potential of these inhibitors and combination approaches."

Preclinical • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Oncology • Solid Tumor • KRAS

Investigating therapeutic strategies to promote immune rejection of KRASG12C inhibitor-resistant subpopulations in lung cancer (EORTC-NCI-AACR 2024) - "KRASG12C inhibition as monotherapy, either with the active-state KRASG12C inhibitor RMC-4998 or the inactive-state inhibitor adagrasib, led to a proliferative advantage of the drug-resistant subpopulation, suggesting that any immune response to KRASG12C inhibition in the bulk tumour population was insufficient to target the resistant cell subclones.To investigate if immune-mediated elimination of resistant cells could be achieved using combinations, we assessed two strategies commonly evaluated in clinical trials with KRASG12C inhibitors: anti-PD1 blockade and SHP2 inhibition...Treatment of RMC-4998 in combination with either anti-PD1 or the SHP2 inhibitor RMC-4550 was able to induce complete eradication of both KRASG12C and KRASG12D mutant lung cancer cells, despite the resistant cells being insensitive to these therapies when treated in the absence of sensitive cells...These long-term effects were dependent on the immune system as they were not observed in..."

Clinical • IO biomarker • Lung Cancer • Oncology • Solid Tumor • KRAS

Combined RASG12C(ON) and SHP2 inhibition promotes an immunogenic tumour microenvironment in lung cancer. (EACR 2024) - "We employ qPCR, Flow Cytometry and RNA sequencing to study the effect of thiscombination on the tumour microenvironment (TME).Results and Discussions KRAS inhibition was followed by MAPK reactivation, which could besuppressed through combination with SHP2 inhibitor RMC-4550 leading to elevated cancer cellapoptosis...Of note, SHP2 inhibition induced a pan-lymphocytic infiltrationindependent of cancer cell intrinsic KRAS signalling, demonstrating the importance of SHP2 inremodelling the TME in a cancer cell extrinsic manner. KRAS and SHP2 combined inhibition led toexclusion of immunosuppressive innate immune cells, expression of antigen presenting andphagocytosis markers, accompanied by activation of lymphocytes expressing tumouricidal cytokinesand proteases.Conclusion Our preclinical data demonstrate that combination of RASG12C and SHP2 inhibitors canremodel the TME eliciting a pan-lymphocytic anti-tumour immune response with a potential benefit intumours that are ICB..."

Tumor microenvironment • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Investigating therapeutic strategies to promote immune rejection of KRASG12C inhibitor-resistant subpopulations in lung cancer (AACR 2024) - "KRASG12C inhibition as monotherapy, either with the active-state KRASG12C inhibitor RMC-4998 or the inactive-state inhibitor adagrasib, led to a proliferative advantage of the drug-resistant subpopulation, suggesting that any immune response to KRASG12C inhibition in the bulk tumor population was insufficient to target the resistant cell subclones...Treatment of RMC-4998 in combination with either anti-PD1 or the SHP2 inhibitor RMC-4550 was able to induce complete eradication of both KRASG12C and KRASG12D mutant lung cancer cells, despite the resistant cells being insensitive to these therapies when treated in the absence of sensitive cells...Immune profiling of treated tumors revealed that both combinations can result in a more profound remodeling of the TME and potentiate the immune responses. Overall, our preclinical results demonstrate that the anti-tumor responses generated by the combination of KRASG12C inhibitors with SHP2 inhibition and/or immune checkpoint..."

Clinical • IO biomarker • Lung Cancer • Oncology • Solid Tumor • KRAS

SHP2 inhibition displays efficacy as a monotherapy and in combination with JAK2 inhibition in preclinical models of myeloproliferative neoplasms. (PubMed, Am J Hematol) - "The combination of RMC-4550 and ruxolitinib, which was safe and tolerated in healthy mice, further inhibited disease compared to ruxolitinib monotherapy, including extending survival. Given SHP2 inhibitors are undergoing clinical evaluation in patients with solid tumors, our preclinical findings suggest that SHP2 is a candidate therapeutic target with potential for rapid translation to clinical assessment to improve current targeted therapies for MPN patients."

Combination therapy • Journal • Monotherapy • Preclinical • Essential Thrombocythemia • Hematological Disorders • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Solid Tumor • Thrombocytosis

Preclinical translational platform of neuroinflammatory disease biology relevant to neurodegenerative disease. (PubMed, J Neuroinflammation) - "Three structurally distinct inhibitors of PTPN11 (RMC-4550, TN0155, IACS-13909) reversed the neuroinflammatory disease signature. Collectively, these results highlight the utility of this novel neuroinflammatory platform for facilitating identification and validation of targets for neuroinflammatory neurodegenerative disease drug discovery."

Journal • Preclinical • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Huntington's Disease • Inflammation • Movement Disorders • DHFR • NLRP3 • PTPN11

Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in FLT3- and KIT-mutant AML. (PubMed, Cell Rep Med) - "Consequently, RMC-4550 and venetoclax are synergistically lethal in AML cell lines and in clinically relevant xenograft models. Our results provide mechanistic rationale and pre-clinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BMF • FLT3 • KIT • MCL1

SHP2 Inhibition Enhances JAK2 Inhibitor Therapy in Preclinical Models of Myeloproliferative Neoplasms (ASH 2023) - "We found that the SHP2 inhibitors RMC-4550 and SHP099 enhanced growth inhibition of MPN model cell lines (e.g., SET2 and UKE1) in combination with ruxolitinib, effectively preventing ruxolitinib persistent growth. Importantly, the combination of SHP2 inhibition using RMC-4550 with JAK2 inhibition using ruxolitinib for 4 weeks in wildtype mice was well tolerated with respect to hematologic parameters and exemplified by no effect on body weight (Panel B). Given SHP2 inhibitors are already undergoing clinical evaluation in patients with solid tumors, our findings suggest that SHP2 is a therapeutic target with potential to be rapidly translated to clinical assessment for MPN patients."

Preclinical • Essential Thrombocythemia • Hematological Disorders • Hematological Malignancies • Hepatology • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Solid Tumor • Thrombocytosis • CALR • CXCL9 • IL1B • TNFA

Single-cell functional genomic analysis of pharmacologic responses in NF1 mutant glioblastoma reveals distinct mechanisms of action for MEK and SHP2 inhibition (SNO 2023) - "In NF1 mutant glioblastoma in vitro and in vivo models, cellular response to both upstream (SHP2) and downstream (MEK) inhibition are mediated by Ras/Raf/MEK signaling while RMC-4550 alone uniquely regulates a focal adhesion network associated with EMT and demonstrates improved efficacy in vivo."

Genomic analysis • Omic analysis • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • NF1

Combining KRASG12C(ON) inhibitor with SHP2 and/or immune checkpoint blockade to overcome adaptive resistance and enhance anti-tumour immunity in lung cancer (SITC 2023) - "3 Methods In this study we use a novel, covalent tri-complex KRASG12C(ON) inhibitor, RM-029, which targets KRASG12C in the active state in combination with the SHP2 inhibitor RMC-4550 (both preclinical tool compounds), and studied their in vivo anti-tumor activity on transplantable KRAS-mutant lung cancer mouse models of varying immunogenicities...Results In vitro, RM-029 exhibited higher potency for inhibition of cell viability than the KRASG12C(OFF) inhibitor MRTX849 in both human and murine NSCLC cell lines...This is accompanied by significant TME reorganization, including depletion of immunosuppressive innate immune cells and recruitment and activation of T and NK cells. Conclusions Overall, our preclinical results demonstrate the potential of the combination of KRASG12C(ON) inhibitors with SHP2 inhibitors and/or immune checkpoint blockade not only by targeting KRAS-driven proliferation in tumour cells but by stimulating anti-tumour immunity."

Checkpoint block • Checkpoint inhibition • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

COMBINATION THERAPY FOR THE TREATMENT OF KRAS-MUTANT PANCREATIC CANCER: PRE-CLINICAL INVESTIGATION OF THE NOVEL INHIBITORS RMC-4550 (SHP2I) AND LY3214996 (ERKI) (UEGW 2023) - P1 | "As a result of our findings, combined inhibition of SHP2 and ERK is currently under investigation in a clinical trial (SHERPA, SHP2 and ERK inhibition in pancreatic cancer, NCT04916236), in patients with KRAS-mutant NSCLC, CRC and PDAC."

Combination therapy • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Transplantation • KRAS

SHP2 participates in decidualization by activating ERK to maintain normal nuclear localization of progesterone receptor. (PubMed, Reproduction) - "SHP2 inhibitor RMC-4550 and shRNA mediated SHP2 reduction resulted in a decreased level of phosphorylation of ERK and aberrant cytoplasmic localization of progesterone receptor (PR), coinciding with reduced expression of IGFBP1 and various other target genes of decidualization...Moreover, reduced expression of SHP2 was detected in decidua of RM patients. Our results revealed that SHP2 is key to PR's nuclear localization, thereby indispensable for decidualization and that reduced expression of SHP2 might be engaged in the pathogenesis of RM."

Journal • IGFBP1 • PGR

Combining KRASG12C(ON) inhibition with SHP2 and immune checkpoint blockade to enhance anti-tumor immunity and overcome development of resistance in lung cancer (AACR 2023) - "Treatment with RM-029 still resulted in some degree of adaptive RAS pathway reactivation, which can be blocked using the SHP2 inhibitor RMC-4550...We find evidence of bystander immune mediated killing of G12Ci-resistant cells in response to the different treatment combinations. Overall, our preclinical results demonstrate the potential of the combination of KRASG12C(ON) inhibitors with SHP2 and/or immune checkpoint blockade not only by targeting KRAS-driven proliferation in tumor cells but by stimulating anti-tumor immunity to target both G12Ci sensitive and resistant cells."

Checkpoint block • Checkpoint inhibition • IO biomarker • Lung Cancer • Oncology • Solid Tumor • KRAS

Evaluation of KRAS inhibitor responses in novel murine KRAS lung cancer cell line models. (PubMed, Front Oncol) - "The three lines exhibit similar in vitro sensitivities to KRAS inhibitors (MRTX-1257, MRTX-849, AMG-510), but distinct in vivo responses to MRTX-849 ranging from progressive growth with orthotopic LLC-NRAS KO tumors to modest shrinkage with mKRC.1 tumors. All three cell lines exhibited synergistic in vitro growth inhibition with combinations of MRTX-1257 and the SHP2/PTPN11 inhibitor, RMC-4550...Notably, single-agent MRTX-849 activity in mKRC.1 tumors and the combination response in LLC-NRAS KO tumors was lost when the experiments were performed in athymic nu/nu mice, supporting a growing literature demonstrating a role for adaptive immunity in the response to this class of drugs. These new models of murine KRAS mutant lung cancer should prove valuable for identifying improved therapeutic combination strategies with KRAS inhibitors."

Journal • Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • NRAS • PTPN11

SHP2 Inhibition Suppresses RAS-ERK Signaling, the Development of JAK2 Inhibitor Persistence, and MPN Development in Pre-Clinical Models of Myeloproliferative Neoplasms (ASH 2022) - "There are three FDA approved JAK2 inhibitors for MPN patients: ruxolitinib, fedratinib and pacritinib...After another week of treatment, we observed while white blood cell counts started going up in monotherapy cohorts, but the combination of ruxolitinib and RMC-4550 continued to suppress cell counts lower than those at the initiation of treatment, and not surprisingly mice treated with the combination therapy ultimately survived significantly longer. These ongoing experiments suggest SHP2 inhibition may enhance the efficacy of ruxolitinib and antagonize the development of JAK2 inhibitor persistence, possibly through greater suppression of RAS-ERK signaling. In summary, these results suggest that inhibition of SHP2 as a monotherapy or in combination with JAK2 inhibition may provide a promising therapeutic approach to improve targeted therapies for MPN patients."

Preclinical • Bone Marrow Transplantation • Hematological Malignancies • Myeloproliferative Neoplasm • Oncology • Transplantation • CALR • GAB1

[PREPRINT] Allosteric SHP2 Inhibition Increases Apoptotic Dependency on BCL2 and Synergizes with Venetoclax in FLT3- and KIT- Mutant AML (bioRxiv) - "Hereby, we report pre-clinical efficacy of co-targeting SHP2, a critical node in MAPK signaling, and BCL2 in RTK-driven AML. The allosteric SHP2 inhibitor RMC-4550 suppressed proliferation of AML cell lines with FLT3 and KIT mutations, including cell lines with acquired resistance to FLT3i. We demonstrate that SHP2 inhibition unveils an Achilles heel of AML, increasing apoptotic dependency on BCL2 via MAPK-dependent mechanisms, including upregulation of BMF and downregulation of MCL1. Consequently, RMC-4550 and venetoclax are synergistically lethal in FLT3- or KIT-mutant AML cell lines, and in clinically relevant xenograft models. Our results provide new mechanistic rationale and preclinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML."

Preclinical • Preprint • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology

Extensive preclinical validation of combined RMC-4550 and LY3214996 supports clinical investigation for KRAS mutant pancreatic cancer. (PubMed, Cell Rep Med) - P1 | "Finally, we show evidence that F-fluorodeoxyglucose (FDG) positron emission tomography (PET) can be used to assess early drug responses in animal models. Based on these results, we will investigate this drug combination in the SHP2 and ERK inhibition in pancreatic cancer (SHERPA; ClinicalTrials.gov: NCT04916236) clinical trial, enrolling patients with KRAS-mutant PDAC."

Journal • Preclinical • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Combination of KRASG12C(ON) and SHP2 inhibitors overcomes adaptive resistance and enhances anti-tumour immunity (AACR-NCI-EORTC 2022) - "In this study we combine a novel covalent tricomplex KRASG12C(ON) inhibitor, RM-029, which targets the GTP-bound active state, with the SHP2 inhibitor RMC-4550 and analyse if treatment can result in favorable changes in the immune tumor microenvironment (TME) which can lead to adaptive anti-tumor immune responses... In vitro, RM-029 exhibited higher potency for inhibition of cell viability than the KRASG12C(OFF) inhibitor MRTX849 in human NSCLC cell lines... Overall, these preclinical data show that both KRASG12C(ON) and SHP2 inhibitors induce significant remodelling of the TME while their combination blocks RAS pathway reactivation, increasing tumour responses and sensitising immune evasive tumours to anti-PD1 blockade."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Allosteric Inhibition of SHP2 rescues functional T-cell abnormalities in SAP deficiency. (PubMed, J Allergy Clin Immunol) - "These data suggest that SHP2 inhibitors could offer a novel and effective targeted treatment approach for XLP patients."

IO biomarker • Journal • Bone Marrow Transplantation • Hematological Malignancies • Immunology • Lymphoma • Oncology • Primary Immunodeficiency • Rare Diseases • Transplantation • CD8

SHP2 Inhibitors Show Anti-Myeloma Activity and Synergize With Bortezomib in the Treatment of Multiple Myeloma. (PubMed, Front Pharmacol) - "In this study, we showed that pharmacological inhibition of SHP2 activity using SHP099 and RMC-4550 efficiently inhibited the proliferation of MM cells by inducing apoptosis and cell cycle arrest. In addition, SHP2 inhibitors synergized the antineoplastic effect of bortezomib in bortezomib-sensitive MM cells and showed identical efficacy in targeting bortezomib-resistant MM cells. Overall, our findings suggest that SHP2-specific inhibitors trigger anti-myeloma activity in vitro and in vivo by regulating the ERK pathway and enhancing cytotoxicity of bortezomib, providing therapeutic benefits for both bortezomib naïve and resistant MM."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • CASP3 • CDKN1A

Combination of KRASG12C(ON) and SHP2 inhibitors overcomes adaptive resistance and enhances anti-tumor immunity (AACR 2022) - "In vitro, the KRASG12C(ON) inhibitor RM-029 exhibited higher efficacy than the KRASG12C(OFF) inhibitor MRTX849 (adagrasib). However, treatment with RM-029 also showed adaptive RAS pathway reactivation after 24 hours of treatment, which can be blocked using the SHP2 inhibitor RMC-4550, suggesting that pathway reactivation is mediated by signaling from RTKs to RAS proteins...Second, both inhibitors have beneficial effects in the TME which can be potentiated when combined. Finally, addition of a SHP2 inhibitor could potentially overcome intrinsic resistant populations by directly targeting cells resistant to G12C inhibition and/or by increasing anti-tumor immunity."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

An allosteric SHP2 inhibitor RMC-4550 induces immunogenicity in pancreatic adenocarcinoma (PDA) and enhances the cytotoxicity of CD8+ effector T cells (AACR 2022) - "SHP2i RMC-4550 and αPD-1 combination induces significant anti-tumor benefit in an in vivo PDA tumor model, an effect that is enhanced by adding gemcitabine. SHP2i may promote antitumor immunity in part by increasing MHC-I expression and reducing PD-L1 expression in RAS mutant PDA cells. PD-L1 mediated suppression of T cell proliferation was overcome by RMC-4550."

IO biomarker • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • CD8 • GZMB • KRAS • PDX1

HBI-2376, HUYABIO clinical stage SHP2 inhibitor, possess robust in vitro potency and in vivo efficacy in several preclinical tumor models carrying KrasG12C or EGFR mutations (AACR 2022) - "Consistently, HBI-2376 found to be more efficacious in tumor growth inhibition than TNO-155 and RMC-4550 in NCI-H1975L858R_T790M_C797S osimertinib-resistant cell line and other tumor models. Furthermore, Western blotting showed inhibition of p-ERK and DUSP6 in HBI-2376 treated cells indicative of a biomarker of response to the therapy. These findings, along with a positive safety profile led to HBI-2376 IND clearance by FDA and suggested promising responses in NSCLC or CRC patients in the forthcoming clinical studies."

IO biomarker • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • DUSP6 • EGFR • KRAS